Full-length Tissue Factor (flTF) is the principal initiator of blood coagulation. Following vascular damage, flTF binds its ligand FVII(a) which triggers clot formation. Aside from sub-endothelial tissues, flTF is also abundant on cancer cells and fuels tumor progression by modulating major signaling pathways; flTF regulates integrin α3β1 function and cell migration, and flTF in complex with FVIIa activates Protease Activated Receptor (PAR)2, while association of flTF with β1 integrins enhances PAR2 activation. flTF-dependent PAR2 activation and integrin regulation result in the production of pro-angiogenic factors such as VEGF, CXCL1 and IL-8, thus promoting the angiogenic switch and, consequently, tumor growth in vivo.
Alternative splicing of TF pre-mRNA yields alternatively spliced TF (asTF). asTF lacks the transmembrane domain and can thus be secreted. In humans and mice, asTF contains a novel C-terminus with poor homology to any known proteins. High expression of asTF expression in tumor cell lines suggests a role in tumor progression. Subcutaneous growth of pancreatic cancer cells overexpressing asTF, results in larger and more vascularized tumors. We recently discovered that asTF induces angiogenesis, independent of PAR2 activation, by acting as an integrin ligand. Thus, flTF and asTF facilitate cellular signaling via distinct mechanisms critical to tumor cell behavior.
Alternative pre-mRNA splicing increases the repertoire of cellular proteins. In cancer cells, such as breast cancer cells, proteins that modulate splicing events such as ASF/SF2 and SRp55, are frequently upregulated and contribute to cell transformation. Breast cancer cells exhibit specific alternative splicing signatures that were proposed as potential prognostic factors in breast cancer. Alternative splicing of proteins such as spleen tyrosine kinase (Syk), p53, PTEN, CXCR3 and Rac1 impacts breast cancer cell behavior and therefore, disease progression.
Currently, nothing is known about asTF expression and function in breast cancer. Regulated splicing of TF pre-mRNA in human monocytes is controlled by several SR proteins, including ASF/SF2 and SRp55. Expression of SR proteins is frequently perturbed in breast cancer tumors, and it is thus plausible that the relative abundance of flTF and asTF is also altered in breast cancer.